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Caledonia.
Roselyne Defay, Isabelle Jaussent, Annie Lacroux, Annick Fontbonne
To cite this version:
Roselyne Defay, Isabelle Jaussent, Annie Lacroux, Annick Fontbonne. Relationships between gly-caemic abnormalities, obesity and insulin resistance in nondiabetic Polynesians of New Caledonia.. Int J Obes (Lond), 2007, 31 (1), pp.109-113. �10.1038/sj.ijo.0803384�. �inserm-00000102�
Relationships between glycaemic abnormalities, obesity, and insulin
resistance in non diabetic Polynesians of New Caledonia.
Running title: Diabetes risk profile in Polynesians 5
R Defay1, I Jaussent2, A Lacroux1, A Fontbonne1, and the CALDIA Study Group
1INSERM, UR024 Epiprev, IRD, F-34394 Montpellier, France; and 2INSERM E0361,
F-34093 Montpellier, France. Correspondence:
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Dr A Fontbonne Current postal address:
IRD–UR 024, 911 avenue Agropolis, BP64501, F-34394 Montpellier Cedex 5, France E-mail: fontbon@montp.inserm.fr
Tel: +(33)467416158 15
Fax: +(33)467416330
Abstract
OBJECTIVE: Polynesians in New Caledonia have an increased risk for developing diabetes,
compared to Melanesians or Europeans. They are also more prone to obesity. The aim of this study was to analyse differences in the pre-diabetic state that may explain the varying susceptibility to diabetes between these three ethnic groups, focusing on the balance between 5
insulin resistance and capacity of pancreatic cells to secrete insulin.
DESIGN AND SUBJECTS: The CALDIA Study is a population-based cross-sectional
survey of diabetes prevalence conducted in New Caledonia. All participants who did not have diabetes, according to the results of a 0-2h oral glucose tolerance test (n=392), were selected for analysis.
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RESULTS: Compared to Europeans, Polynesians and Melanesians had significantly higher
body mass indices (BMI) and waist-to-hip ratios (WHR). Polynesians had higher fasting plasma glucose values than Europeans or Melanesians (6.03 mmol/l, vs 5.78 and 5.46, respectively; P<0.0001). Fasting plasma insulin level and the estimate of insulin resistance by homeostasis model assessment (HOMA) were not significantly different between the three 15
ethnic groups. HOMA estimate of β-cell secretory capacity was lower in Polynesians compared to the two other ethnic groups (83.1 mU/mmol, vs 119.3 and 125.2, respectively; P<0.02).
CONCLUSION: Despite a high prevalence of central obesity, as judged by high BMI and
WHR, in Polynesians of New Caledonia, their high risk of diabetes may be more strongly 20
related to a defect in insulin secretion capacity than to insulin resistance.
Keywords: epidemiology; Polynesians; insulin resistance; insulin secretion; type 2 diabetes
Introduction
Type 2 diabetes is considered to be the result of a two-step process.1 In the first “ prediabetic ” step characterised by insulin resistance, compensatory hyperinsulinaemia helps maintain normal glucose levels. In the second step there is a decline in β-cell secretory capacity together with a progressive elevation of glucose levels which define diabetes.2 This 5
two-step mechanism has been shown to apply to many populations around the world (e.g., Pima Indians, Micronesians, Mexican Americans, South Asians).3 However, the balance between insulin resistance and deficient insulin secretion in the pathogenesis of type 2 diabetes appears to vary between ethnic groups.4 Regarding Polynesians, a population with a high prevalence of obesity and diabetes, one study in New Zealand reported that, after 10
adjustment for body mass index, Polynesians were not more insulin-resistant than Europeans, who are much less susceptible to diabetes.5
Previous publications from the CALDIA Study, a large diabetes screening survey conducted in the multi-ethnic population of New Caledonia, have shown that Polynesians indeed had the highest degree of central obesity, and the highest prevalence rate of diabetes 15
compared to the other two major ethnic groups living in the archipelago (15.3%, vs 8.4% in Melanesians or Europeans).6,7 In order to further examine the abnormalities that could explain their higher risk of diabetes, we selected from the CALDIA database non diabetic subjects with the purpose of comparing the degree of insulin resistance and of β-cell secretory capacity (using the homeostasis model assessment, or HOMA) between ethnic groups.
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Population and methods
The CALDIA Study was conducted from 1992 to 1994 to determine the prevalence of diabetes in New Caledonia. The rationale, design and methods of the study were previously described in detail.6 To summarise, the target population for the CALDIA Study were subjects
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aged 30-59, resident in New Caledonia for more than 10 years. Subjects were recruited all over the territory (North province, Noumea, and Loyalty Islands). In the North province, 12 small towns and 101 villages out of 199 were randomly selected. In Noumea, six suburbs were chosen because they included all the ethnic groups. In the Loyalty Islands, all 85 villages participated. As a whole, 9390 subjects (representing a response rate of 78%) were visited at 5
home for screening, where they all had a capillary blood glucose (CBG) measurement with a reflectance meter (One Touch®, LifeScan). All previously known diabetic subjects and subjects having a CBG value ≥6.1 mmol/l when fasting, or CBG ≥7.8 mmol/l when non fasting (n=643), were invited to come to the health centre for a more detailed examination. The response rate for this examination was 91.5% (588 subjects). At the same time, a 10
selection of 517 subjects with CBG <6.1 mmol/l, matched by ethnic group, gender, age, and location, also underwent the examination.
At the health centre, participants answered a standardised questionnaire and underwent anthropometric measurements. Body mass index (BMI=weight (kg)/height (m)2) was used to report general obesity. According to the World Health Organization (WHO) criteria,8 subjects
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with BMI 25-29.9 were considered overweight and subjects with BMI ≥30 were classified as obese. Waist and hip circumferences were measured in the standing position to the nearest cm, the first at the umbilicus, the second at the iliac crest. The waist-to-hip ratio (WHR) was calculated as an index of upper-body adiposity.
A two-hour oral glucose tolerance test (OGTT) with a 75-g glucose load was 20
performed according to the WHO recommendations.9 Blood samples were locally centrifuged, frozen and sent to Noumea central laboratory. Fasting plasma glucose (FPG) and 2-hour plasma glucose (2h-PG) levels were assessed by the glucose oxidase method in Noumea. Fasting plasma insulin (FPI) was measured by radioimmunoassay (RIAgnost, Behring, Los Angeles, CA) at the Henri Mondor Hospital, Créteil, France.
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The study protocol and procedures were approved by all local medical commissions involved, and all participants gave informed consent for their participation.
Among the 1105 subjects having a complete examination, we excluded diabetic subjects, known or newly diagnosed, that is having FPG ≥7 mmol/l or 2h-PG ≥11.1 mmol/l at the OGTT.9 One unclassified subject was also excluded. Of the remaining subjects, only those 5
of European, Melanesian, or Polynesian origin were retained. Subjects were classified as normoglycaemic (FPG <6.1 mmol/l and 2h-PG <7.8 mmol/l), having impaired fasting glucose (IFG) (6.1 mmol/l ≤FPG <7.0 mmol/l and 2h-PG <7.8 mmol/l), or impaired glucose tolerance (IGT) (7.8 mmol/l ≤2h-PG <11.1 mmol/l, irrespective of FPG values).9 To assess insulin resistance and β-cell function, the homeostasis model assessment (HOMA),10 was applied to
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fasting plasma glucose and insulin values as follows: insulin resistance (HOMA-IR)=FPI (mU/l)xFPG (mmol/l)/22.5; β-cell function (HOMA-BC)=[20xFPI (mU/l)]/[FPG (mmol/l)-3.5].
Age, sex, anthropometric variables and variables characterising glucose-insulin regulation were compared between the three ethnic groups using χ2 test for categorical 15
variables and analysis of variance for continuous variables. Glucose homeostasis variables were also compared after multiple adjustment for age, sex and BMI, by analysis of covariance. When comparisons were statistically significant, two-by-two comparisons were carried out, using the Bonferroni correction. Continuous variables with a log-normal distribution were log-transformed before testing, and back-transformed into natural values for 20
presentation. All statistical analyses were performed with SAS statistical package software version 9.1 (SAS Institute, Cary, NC).
Results
After exclusion of subjects with missing values for the variables of interest, analysis 25
was performed on 392 subjects (57 Europeans, 287 Melanesians, 48 Polynesians). Their general characteristics are shown in Table 1. Age and sex distribution were not significantly different between the groups. Mean BMI and WHR were highest in Polynesians and lowest in Europeans. Overweight and obesity were significantly more prevalent (P<0.0001) in Polynesians or Melanesians than in Europeans.
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Non-adjusted and age, sex and BMI-adjusted comparisons of variables characterising glucose-insulin regulation are shown in Table 2. Fasting plasma glucose values were significantly different between the three groups, with the highest mean value observed in Polynesians, who also had the highest prevalence rate of glycaemic anomalies (IFG or IGT: 43.7%, vs 35.1% in Europeans and 22.6% in Melanesians, P<0.01). Non-adjusted two-hour 10
plasma glucose was not significantly different between the three groups, but the differences became significant when adjusted for age, sex and BMI. Despite the marked differences in morphotype between the groups, the geometric means of fasting insulin and HOMA-IR were not significantly different. By contrast, there was a significant difference (P<0.02) for the marker of insulin secretion capacity, HOMA-BC, with the lowest value observed in 15
Polynesians. When the analysis was performed after adjustment for BMI, the differences became significant for FPI (P<0.004) and HOMA-IR (P<0.002). The two-by-two comparisons with Bonferroni adjustment (Table 3) indicated that for these markers of insulin resistance, the differences were between Europeans and the two other ethnic groups, with Europeans having significantly higher indices of insulin resistance. By contrast, insulin secretory 20
capacity was significantly lower in Polynesians compared to the two other ethnic groups. To better understand this finding, the three ethnic groups were divided according to BMI (normal, overweight or obese). At any given body mass, Polynesians had the highest fasting glucose values together with the lowest fasting insulin values, denoting a clear lack of insulin, both absolute and relative to glucose values (Figure 1, panels A and B). This was 25
confirmed by the fact that the curve for HOMA-BC in Polynesians was consistently and largely lower, at any given body mass, compared to the two other groups (Figure 1, panel C).
Discussion
Polynesians are known to be a population at high risk for type 2 diabetes. This was 5
confirmed in the CALDIA study, where diabetes prevalence rate was twice that observed in Europeans or Melanesians.6 Moreover, in our analysis restricted to non-diabetic subjects, Polynesians were markedly overweight with upper-body obesity, and they already exhibited abnormalities of glucose homeostasis (higher FPG values and lower prevalence of normoglycaemic subjects), which are signs of susceptibility to diabetes.11 While obesity is 10
commonly associated with insulin resistance and hyperinsulinaemia, and the classical view is that these anomalies are markers of the prediabetic state,12-14 the only accompanying anomaly we found in Polynesians was a relative defect in insulin secretion. The fact that our radioimmunoassay was not specific for insulin does not challenge the finding, since, if there are differences of proinsulin proportion between the study groups, it is probably higher in 15
Polynesians given their “worse” glucose homeostasis. After adjustment for BMI, insulin sensitivity in both Polynesians and Melanesians was actually greater than in Europeans. Although we used an indirect method (HOMA) for estimation of insulin secretion and insulin resistance, the HOMA indices have been validated against the glucose clamp, for various degrees of glucose tolerance and plasma insulin levels,15 and have been largely used in 20
epidemiological studies.5,16
Our results are consistent with those of Simmons et al., who found that Polynesians of New-Zealand were not “ intrinsically insulin resistant ” despite a high prevalence rate of diabetes and a greater central and overall obesity compared to Europeans of the same area.5 In their study, although Polynesians had significantly higher markers of insulin resistance in 25
univariate comparisons, there were no differences after adjustment for BMI (in our study, this was the case even before adjustment for BMI).
Altogether, these two studies suggest that in Polynesians, the progression from normal glucose tolerance to type 2 diabetes may not include an insulin resistance state characterised by compensatory hyperinsulinaemia. It is already known that the pathogenesis of type 2 5
diabetes is a combination of insulin resistance and reduced insulin secretion,2 and the predominant mechanism is possibly different in various ethnic groups.4 Our study points out to pancreatic deficiency being the main anomaly taking part in the Polynesians’ high susceptibility to diabetes mellitus. However, the absence of a frank defect of insulin sensitivity is unexpected, given their general morphotype, since excess adiposity is normally 10
accompanied by insulin resistance17 and decrease in insulin sensitivity is even considered a regulatory response to weight gain, which it serves to limit.18 Of course, we cannot exclude that HOMA-IR is not a correct estimate of insulin resistance in this ethnic group, although it has been validated in subjects with normal to low insulin concentrations at least in one study.15 Besides, fasting plasma insulin levels and insulin sensitivity are reciprocally related,
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19 making it unlikely that Polynesians would actually be insulin resistant while they have
normal insulin levels. If we consider that Polynesians are truly not insulin resistant, one explanation may be that BMI is not a good estimate of adiposity in this particular ethnic group. Indeed, the universal BMI standards for defining “ overweight ” and “ obesity ” in adults are based on the risk of adiposity-related diseases in Caucasians,20 and this may not
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apply to all populations. For instance, in a meta-analysis about ethnic differences in the associations between BMI and percent body fat, Polynesians had the highest mean BMI whereas their degree of body fatness was below that of some ethnic groups such as Indonesians, Thais or Ethiopians.21 Another study showed that, at higher BMI levels, Polynesians had significantly more lean mass than Europeans.22 Another possible explanation
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is that, since Polynesians in New Caledonia are generally employed in heavy, energy-consuming work, this may significantly enhance their insulin sensitivity.4,23 Also, it cannot be excluded that Polynesians have an insulin-deficient form of diabetes, different from type 2.2,24,25
Whatever the explanation, if it is confirmed that insulin resistance in the prediabetic 5
state is not the prominent anomaly in this ethnic group (and maybe others), a new approach to the prevention of type 2 diabetes should be designed.
Acknowledgements
We thank each member of the CALDIA Study Group who permitted the design and/or 10
conduction of the CALDIA Study. Coordination, INSERM - in France: L Papoz (principal coordinator), D Simon, J Cubeau, A Lacroux, A Forhan and A Ponton; in New Caledonia: S Barny (local coordinator), D Juranville, H Lmahdi and R Manuohalalo. Health and Social Services in New Caledonia - Medical and Research Commission: F Ledoux and C Merger; Territory: M Germain; North Province: P Calen and P Genty; Loyalty Islands: J Coscoquela 15
and P Buffet; South Province: JG Lambert and P Baqué; and Biochemistry (Territorial Hospital): S Solar and Y Barguil.
We thank V Wirquin of the Henri Mondor Hospital Laboratory (Créteil, France) for the measures of fasting plasma insulin.
This research was financed by grant 492015 from the INSERM (Institut National de la Santé 20
et de la Recherche Médicale), grant 607006 from the French Ministry of Cooperation, with additional support from the Medical Commission and the Provinces of New Caledonia, the Rotary and Lions Clubs of Noumea, and Behring Diagnostic Laboratory.
Title and legend to figure
Figure 1. Levels of fasting plasma glucose (FPG, panel A), fasting plasma insulin (FPI, panel
B) and HOMA estimate of β-cell function (HOMA-BC, panel C) by degree of overweight in non diabetic Europeans, Melanesians, and Polynesians in New Caledonia.
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Europeans Melanesians Polynesians n =57 n = 287 n = 48 p Age (years) 47.1 (45.2-49.0) 47.0 (46.1-47.8) 47.9 (45.6-50.1) NS Men 23 (40.4) 96 (33.5) 16 (33.3) NS BMI (kg/m2): <25 27 (47.4) 57 (19.9) 13 (27.1) <0.0001 25-29 22 (38.6) 120 (41.8) 15 (31.2) ≥30 8 (14.0) 110 (38.3) 20 (41.7) Meana 25.5 (24.6-26.5) 28.7 (28.1-29.2) 29.0 (27.2-31.0) <0.0001 WHR 0.89 (0.86-0.91) 0.92 (0.91-0.93) 0.94 (0.92-0.96) <0.001 Ethnic group a
Log-transform applied. BMI, body mass index. WHR, waist-to-hip ratio.
Europeans Melanesians Polynesians n =57 n = 287 n = 48 pb pc FPG (mmol/l) 5.78 (5.62-5.93) 5.46 (5.38-5.54) 6.03 (5.89-6.18) <0.0001 <0.0001 2h-PG (mmol/l)a 5.99 (5.59-6.42) 5.68 (5.50-5.87) 6.11 (5.72-6.53) NS <0.03 Glucose tolerance: Normal 37 (64.9) 222 (77.4) 27 (56.3) <0.01 <0.002 IFG 12 (21.1) 40 (13.9) 17 (35.4) IGT 8 (14.0) 25 (8.7) 4 (8.3) FPI (pmol/l)a 78.3 (63.0-97.3) 67.0 (60.6-74.1) 61.7 (49.7-76.6) NS <0.004 HOMA-IRa 3.33 (2.67-4.15) 2.68 (2.42-2.98) 2.75 (2.19-3.45) NS <0.002 HOMA-BCa 119.3 (94.7-150.3) 124.8 (112.2-138.9) 83.1 (68.0-101.5) <0.02 <0.002 Ethnic group a
Log-transform applied.bcrude.ccovariance analysis with age, sex and BMI as adjusted covariables. FPG, fasting plasma glucose. 2h-PG, 2 hour-plasma glucose. IFG, impaired fasting glucose. IGT, impaired glucose tolerance. FPI, fasting plasma insulin. HOMA-IR and HOMA-BC, homeostasis model assessment of insulin resistance and ß-cell secretory capacity. NS, not significant.
Europeans vs Melanesians Europeans vs Polynesians Melanesians vs Polynesians FPG <0.0003 NS <0.0001 2h-PG <0.05 NS NS FPI <0.007 <0.007 NS HOMA-IR <0.001 <0.02 NS HOMA-BC NS <0.004 <0.003 Ethnic group
